Regulation of the sumoylation system in gene expression

Abstract

SummaryProtein sumoylation has emerged as an important regulatory mechanism for the transcriptional machinery. Sumoylation is a highly dynamic process that is regulated in response to cellular stimuli or pathogenic challenges. Altered activity of the SUMO conjugation system is associated with human cancers and inflammation. Thus, understanding the regulation of protein sumoylation is important for the design of SUMO-based therapeutic strategies for the treatment of human diseases. Recent studies indicate that the sumoylation system can be regulated through multiple mechanisms, including the regulation of the expression of various components of the sumoylation pathway, and the modulation of the activity of SUMO enzymes. In addition, extracellular stimuli can signal to the nucleus to trigger the rapid promoter recruitment of SUMO E3 ligases, resulting in the immediate repression of transcription. Finally, the sumoylation system can also be regulated through crosstalk with other posttranslational modifications, including phosphorylation, ubiquitination, and acetylation.

Adenovirus E1B 55-Kilodalton Protein Is a p53-SUMO1 E3 Ligase That Represses p53 and Stimulates Its Nuclear Export through Interactions with Promyelocytic Leukemia Nuclear Bodies

“…SUMOs are added to specific proteins by an enzymatic pathway analogous to the protein ubiquitination pathway, with a single E1 SUMO-activating enzyme (the SAE1/SAE2 heterodimer in humans), a single E2 SUMO-conjugating enzyme (UBC9), and E3 SUMO protein ligases that direct the charged E2 to sumoylate specific lysines on specific target proteins (34,66). Modification of transcription factors by SUMO can have diverse effects, including targeting to subnuclear compartments (such as PML-nb) (34) and repression of transcriptional activity (51,61,81). A remarkable aspect of this process is that the steady-state level of sumoylation of many transcription factors is often extremely low when repression is maximal, on the order of a few percent of the total cellular protein in question, probably because SUMO groups are rapidly removed after their addition (9,34).…”

Transcriptional ERRγ2-mediated activation is regulated by sentrin-specific proteases

“…In addition to a regulation by phosphorylation, our data is suggestive of an ERRγ regulation through control of the SUMO pathway itself. Accumulating evidence shows that target sumoylation is affected by regulated expression of various components of the sumoylation pathway [39]. Namely PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)] proteins promote SUMOylation of transcription factors in a manner that resembles the action of RINGtype ubiquitin E3 ligases [40].…”

“…Mutagenesis of the RF-1 in the context of a GAL4 fusion protein revealed that all mutants proposed to inhibit sumoylation led to a higher activity of the AF-1. Similarly, a Lys 40 to arginine mutant, as well as the mutation of the hydrophobic residue Ile 39 and of the acidic residue Glu 42 to alanine led to higher activity of full-length ERRγ2. Both, superactivation by replacing the potential phosphorylation acceptor Ser 45 with alanine and a phosphorylation-dependent mobility shift of protein DNA complexes during gel electrophoresis speak in favor of a functional PDSM.…”

MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence

“…The total expression of major ESR1 transcription factors, including p53, SP1, and c-Jun, was also unchanged (Supplemental Figure 9D). MEL-18 functions as an anti-SUMO E3 ligase by directly binding to both UBC9 and its substrate (19,20), and the SUMOylation of transcription factors is often involved in transcriptional inhibition (33). Therefore, we hypothesized that MEL-18 may regulate ESR1 transcription via the inhibition of SUMOylation.…”